The principal goal of this new research program is to design, synthesize and deliver a series of pilot-scale libraries comprised of structurally diverse "natural product-like" compounds to the NIH Molecular Libraries Small-Molecule Repository (MLSMR) for high throughput screening. Toward this end, the PI has assembled a highly experienced, interdisciplinary team of investigators, including synthetic, medicinal and chemical informatics scientists, to assure that members of the proposed pilot scale libraries will cover broad areas of structural diversity not currently found in the NIH Small-Molecule Repository (vide infra), while at the same time having the requisite physiochemical and pharmacokinetic properties to be of value as probes for the exploration of biological systems at the molecular level. Particular emphasis will be placed on carbon-based libraries comprised of enantio- and diastereomerically pure natural product-like compounds. The specific synthetic tactics to be employed have their foundation in three exciting, new and efficient synthetic protocols developed recently in our laboratory, which, when employed in conjunction with the powerful synthetic tactics of ring closing metathesis (RCM), macrolactonization, and/or macrodimerization, hold great promise for the ready construction of diverse organic molecules that mimic both the architecture of complex natural products and their important bio-regulatory properties. The synthetic methods include: (a) Anion Relay Chemistry (ARC), (b) the Petasis-Ferrier Union/Rearrangement, and (c) the Chemo- and Stereoselective Functionalization of Polyenes Possessing Electron-Withdrawing Termini. Using these methods, we propose the synthesis of eight pilot-scale "natural product-like" libraries including macrocarbacycles, macrolactones, tetrahydropyran-based, and alkaloid-like examples. When complete, the carefully designed libraries, exploiting the combined expertise of this consortium of scientists, should significantly augment the diversity of potential small probe molecules currently available to the NIH Small-Molecule Repository.